This invention relates to pyrimidine derivative compounds and pharmaceutically acceptable salts thereof. More specifically, this invention relates to furo[2,3-d]pyrimidines, pyrrolo[2,3-d]pyrimidines, pyrrolo[3,2-d]pyrimidines, pyrrolo[3,4-d]pyrimidines, thieno[2,3-d]pyrimidines, cyclopentapyrimidines, cyclopenta[d]pyrimidines, pyrido[2,3-d]pyrimidines and pyrido[3,2-d]pyrimidines. xe2x80x9cPyrimidine derivativesxe2x80x9d as used herein generally refers to all of these types of compounds. These compounds have been found useful in resisting and treating Pneumocystis carinii, Toxoplasmosis gondii, Mycobacterium tuberculosis and Mycobacterium avium complex (MAC) infections in immunocompromised patients, such as, for example, patients with autoimmune deficiency syndrome (AIDS). These compounds are also useful as potential antitumor, antituberculosis, anti-Mycobacterium avium, antibiotic, antimalarial, antifungal or antiprotozoal agents, or as synergistic agents when used with sulfonamides or other compounds and may require the use of leucovorin rescue. These compounds are also useful as antitumor agents in cancer patients. Methods of preparing and using these compounds are also provided.
Various pyrimidine systems, such as the pyrido[2,3-d]pyrimidine ring system, have been studied due to their involvement in the inhibition of dihydrofolate reductase (DHFR) enzymes activity. The pyrimidine derivatives disclosed herein function as DHFR inhibitors. Because DHFR reduces dihydrofolate to tetrahydrofolate, inhibition of DHFR deprives the cell of tetrahydrofolate, without which the cell cannot produce 5,10-methylenetetrahydrofolate. 5,10-Methylenetetrahydrofolate is essential for cell growth. The inhibition of DHFR by the compounds, and pharmaceutically acceptable salts thereof, of this invention therefore results in the inhibition of DNA synthesis and leads to cell death. Methotrexate (MTX), trimetrexate (TMQ), piritrexim (PTX) and other folic acid analogues function as inhibitors of cell growth by similar mechanisms involving the inhibition of dihydrofolate reductase.
The pyrimidine derivatives disclosed herein also function as thymidylate synthase (TS) inhibitors. TS, along with DHFR, forms part of the systems responsible for the synthesis of deoxythymidylate (dTMP) from deoxyuridylate (dUMP). TS catalyzes the sole de novo synthesis of dTMP from dUMP. Inhibition of TS, therefore, deprives the cell of thymidine, which is an essential constituent of DNA. Typically, the compounds as described herein where X and Y are both NH2 or where X is NH2 and Y is H or CH3 and will function as DHFR inhibitors, and compounds where X is OH and Y is NH2, H, or CH3 will function as TS inhibitors, although the inventor does not wish to be bound by this generality.
Drugs useful for the reduction of cancerous cells are also known.
Elslager, Edward F., et al., xe2x80x9cFolate Antagonists. 20. Synthesis and Antitumor and Antimalarial Properties of Trimetrexate and Related 6-[(Phenylamino)methyl]-2,4-quinazolinediaminesxe2x80x9d J. Med. Chem., Vol. 26 pp. 1753-1760 (1983)), discloses the preparation of quinazolinediamines. This article states that the quinazolinediamines exhibit potent antimalarial, antibacterial and antitumor activity.
Methods of synthesizing diaminopyrido[2,3-d]pyrimidines having various substituents are known. See Hurlbert, B. S., et al., xe2x80x9cStudies on Condensed Pyrimidine Systems. XXIII. Synthesis of 2,4-Diaminopyrido[2,3-d]pyrimidines from xcex2-Keto Estersxe2x80x9d, J. Med. Chem., Vol. 11, pp. 703-707 (1968), and Hurlbert, B. S., and Valenti, B. F., xe2x80x9cStudies on Condensed Pyrimidine Systems. XXIV. The Condensation of 2,4,6-Triaminopyridimine with Malondialdehyde Derivativesxe2x80x9d, J. Med. Chem., Vol. 11, pp. 708-710 (1968).
Hurlbert, B. S., et al., xe2x80x9cStudies on Condensed Pyrimidine Systems. XXV. 2,4-Diaminopyrido[2,3-d]pyrimidines. Biological Dataxe2x80x9d, J. Med. Chem., Vol. 11, pp. 711-717 (1968), discloses the antimicrobial activities of several subgroups of pyridopyrimidines. This article states that 2,4-diaminopyrido[2,3-d]pyrimidines bearing alkyl and aralkyl substituents in the pyrimidine moiety are inhibitors of dihydrofolate reductase having antibacterial and antiprotozoal activity and that these compounds potentiate sulfonamides.
Grivsky, E. M., et al., xe2x80x9cSynthesis and Antitumor Activity of 2,4-Diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyridiminexe2x80x9d, J. Med. Chem., Vol. 23, pp. 327-329 (1980), discloses the synthesis of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyridimine(BW301U,7). This article states that BW301U,7 is as effective as methotrexate as an inhibitor of dihydrofolate reductase purified from human leukemic cells and, in contrast to metoprine, has minimal activity as an inhibitor of histamine metabolism.
Shih et al., xe2x80x9cLY231514, a Pyrrolo[2,3-d]pyrimidine-based Antifolate That Inhibits Multiple Folate-requiring Enzymesxe2x80x9d, Cancer Research, Vol. 57, pp. 1116-1123 (1997) teaches a pyrrolo [2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. A classical or glutamic acid substituted pyrrolo pyrimidine is disclosed.
Taylor et al., xe2x80x9cA Dideazatetrahydrofolate Analogue Lacking a Chiral Center at C-6, N-[4-[2-(2-Amino-3,4-dihydro4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl) ethyl]benzoyl]-L-glutamic Acid, Is an Inhibitor of Thymidylate Synthasexe2x80x9d, J. Med. Chem., Vol. 35, pp. 4450-4454 (1992) also teaches a classic pyrrolo pyrimidine compound useful in the inhibition of thymidylate synthase. Taylor reports other pyrrolo pyrimidine compounds in U.S. Pat. Nos. 4,996,206; 5,028,608; 5,248,775; 5,254,687; and 5,344,932.
Werbel, Leslie, M., et al., xe2x80x9cSynthesis and Antimalarial Activity of a Series of 2,4-Diamino-6-[(N-alkylanilino)methyl]quinazolines [1,2]xe2x80x9d, J. Heterocyclic Chem., Vol. 24, pp. 345-349 (1987), discloses the synthesis of N6 substituted quinazoline dihydrofolate reductase inhibitors. This article states that these analogs demonstrate substantial activity against Plasmodium berghei infections in mice.
Piper, J. R., et al., xe2x80x9cSyntheses and Antifolate Activity of 5-Methyl-5-deaza Analogues of Aminopterin, Methotrexate, Folic Acid, and N10-Methylfolic Acidxe2x80x9d, J. Med. Chem., Vol. 29, pp. 1080-1087 (1986), discloses that 5-methyl-5-deaza analogues of aminopterin and methotrexate are much more growth inhibitory than methotrexate.
Pyrido [2,3-d] and [3,2-d] pyrimidines are also disclosed in U.S. Pat. Nos. 5,346,900 and 5,508,281, and co-pending application Ser. Nos. 08/515,491 and 08/660,023 all of which are hereby expressly incorporated by reference.
Pyrrolo[2,3-d]pyrimidines are disclosed by Gangjee et al. in xe2x80x9cNovel 2,4-diamino-5-substituted-pyrrolo[2,3-d]pyrimidines As Classical and Non-Classical Antifolate Inhibitors of Dihydrofolate Reductasesxe2x80x9d, J. Med. Chem., Vol. 38, pp. 2158-2165 (Jun. 6, 1995).
Gangjee, A., et al., xe2x80x9cClassical and Non-Classical Furo[2,3-d]Pyrimidines As Novel Antifolates: Synthesis and Biological Activitiesxe2x80x9d, J. Med. Chem., Vol. 37, pp. 1169-1176 (1994), discloses furo[2,3-d]pyrimidines.
Mavandadi, et al., disclose 5-substituted classical and nonclassical 2,4-diaminopyrrolo[2,3-d]pyrimidines as antitoxoplasma, antipneuomocystis and antitumor agents in J. Med. Chem., 40:1173-1177 (1997). Mavandadi, et al. also disclose use of pyrrolo[2,3-d]pyrimidines as nonclassical inhibitors of thymidylate synthase in J. Med. Chem., 39:4563-4568 (1996).
There remains a very real and substantial need for compounds that are more active and more selective than known compounds at resisting and treating infections caused by Pneumocystis carinii and Toxoplasmosis gondii, and other organisms in immunocompromised patients, reducing the tumor size and/or the number of cancerous cells in cancer patients, and for methods of preparing and using such compounds.
The present invention has met the above described need by providing potent and selective pyrrolo[2,3-d]pyrimidine compounds and furo[2,3-d]pyrimidine compounds.
Methods of synthesizing the above compounds are also disclosed.
This invention provides methods for therapeutically and/or prophylactically using the compounds, and pharmaceutically acceptable salts and prodrugs thereof, described herein. More specifically, this invention provides methods of using the present pyrimidine derivatives for therapeutic and prophylactic purposes including employing these compounds to resist and treat secondary infections caused by Pneumocystis carinii, Toxoplasmosis gondii, Mycobacterium tuberculosis and Mycobacterium avium complex or other organisms in immunocompromised patients, such as for example patients with AIDS. The immunocompromised patient has a primary infection caused by a retrovirus, including for example, human immunodeficiency virus (HIV). In addition, this invention provides methods of using pyrimidine derivatives as antitumor, antituberculosis, anti-Mycobacterium avium complex, antibiotic, antimalarial, antifungal and antiprotozoal agents and as synergistic agents with sulfonamides in such patients.
This invention also provides methods of using pyrimidine derivatives for therapeutic and/or prophylactic purposes as antitumor agents or to otherwise destroy or minimize growth or proliferation of cancerous cells in cancer patients.
It is an object of this invention to provide pyrimidine derivative compounds, and pharmaceutically acceptable salts thereof, for substantially inhibiting dihydrofolate reductase enzymes.
It is an object of this invention to provide pyrimidine derivative compounds, and pharmaceutically acceptable salts thereof, for substantially inhibiting thymidylate synthase enzymes.
It is an object of the present invention to provide pyrimidine derivative compounds, and pharmaceutically acceptable salts thereof, having antitumor, antituberculosis, anti-Mycobacterium avium complex, antibiotic, antimalarial, antifungal or antiprotozoal activity including synergistic activity with sulfonamides and/or other agents.
It is a further object of this invention to provide pyrimidine derivative compounds, and pharmaceutically acceptable salts thereof, having effective activity against secondary infections, such as for example infections caused by Pneumocystis carinii, Toxoplasmosis gondii, Mycobacterium tuberculosis and Mycobacterium avium complex that occur in immunocompromised patients, such as patients with AIDS.
It is another object of this invention to provide pyrimidine derivative compounds, and pharmaceutically acceptable salts thereof, having effective activity against tumors and other cancerous cells, such as those caused by cancer.
It is an object of this invention to provide a method of synthesizing various pyrimidine derivative compounds, and pharmaceutically acceptable salts thereof.
It is a further object of this invention to provide methods of using in a patient a therapeutically effective amount of pyrimidine derivative compounds, or pharmaceutically acceptable salts thereof.
It is a further object of this invention to provide methods of using in a patient a prophylactically effective amount of pyrimidine derivative compounds, or pharmaceutically acceptable salts thereof.
These and other objects of the invention will be more fully understood from the drawing and the following description of the invention and the claims appended hereto.